Study Finds Novel Gene Associated With Alzheimer’s Disease Development

In a study recently published in the journal Brain a team of researchers found an immune system gene associated with higher rates of amyloid plaque buildup in the brains of patients with Alzheimer’s Disease and older adults at risk for the condition.

The mechanisms underlying amyloid accumulation, the known cause of Alzheimer’s disease (AD), are not fully understood. Pathogenic mutations causing rare, early-onset forms of AD have been described in three genes involved in amyloidogenesis, APP (amyloid precursor protein), PSEN1 and PSEN2. For late-onset AD, the strongest known genetic risk factor is the APOE e4 allele. Several mechanisms have been proposed linking APOE e4 to enhanced aggregation and reduced clearance of brain amyloid. However, APOE e4 is neither necessary nor sufficient for the development of amyloid pathology or incident AD, suggesting that other contributing factors remain to be discovered.

In the study entitled “GWAS of longitudinal amyloid accumulation on ¹⁸F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP”, the multi-institutional research team led by scientists at the Indiana University School of Medicine performed a genome-wide association study of longitudinal change over two years in brain amyloid burden measured by positron emission tomography imaging in nearly 500 subjects.

The researchers identified a novel association between a variant of the IL1RAP gene and greater amyloid plaque accumulation over two years with an even stronger effect than the well-known APOE e4 allele, associated with AD development. However, the team was surprised to discover that IL1RAP, which codes for the immune signaling factor Interleukin-1 Receptor Accessory Protein, exhibited an independent and even stronger effect on the accumulation of amyloid plaque. “This was an intriguing finding because IL1RAP is known to play a central role in the activity of microglia, the immune system cells that act as the brain’s “garbage disposal system” and the focus of heavy investigation in a variety of neurodegenerative diseases,” Vijay K. Ramanan, M.D., Ph.D., postdoctoral researcher at the IU School of Medicine, said in a news release.

The results demonstrated that the amyloid-associated IL1RAP variant was also associated with:

• An inferior level of activity in the microglia assessed with the use of PET scans;
• A superior temporal cortex atrophy (a brain area involved in memory);
• Faster decline in cognitive function;
• Study individuals were more likely to progress from mild cognitive impairment to AD.

“These findings suggest that targeting the IL1RAP immune pathway may be a viable approach for promoting the clearance of amyloid deposits and fighting an important cause of progression in Alzheimer’s disease,” said Andrew Saykin, Psy.D., director of the Indiana Alzheimer Disease Center and the national Alzheimer’s Disease Neuroimaging Initiative Genetics Core.

Dr. Saykin mentioned that existing drugs targeting the IL-1/IL1RAP pathway are currently available for inflammatory and rheumatologic diseases. There are also antibodies against IL1RAP that are currently being evaluated as treatments of certain types of leukemia. Dr. Saykin further said that those tools could be tailored for laboratory investigations to evaluate their potential for the treatment of AD. “The biological roles of IL1RAP in amyloid deposition and clearance, particularly in relation to microglial function, merit further investigation and may have significant implications for risk stratification and therapeutic development in Alzheimer’s disease”, the researchers concluded.